Tocilizumab in Chronic Inflammatory CPPD Disease

Calcium pyrophosphate deposition (CPPD) disease affects 4 to 7% of the adult population. CPP crystals are responsible for inflammatory flares affecting one or more joints. The inflammation triggered by CPP crystals resembles that associated with sodium urate crystals in gout and depends on inflammatory cytokines such as interleukins (IL-) 1β and -6. The usual treatments are those used in gout flares (colchicine, NSAIDs, corticosteroids, IL-1β inhibitors), and most often control monoarticular involvement. The chronic inflammatory polyarticular form, on the other hand, is more difficult to treat, causing significant pain and disability, as well as joint destruction. In refractory forms, or in cases of intolerance to standard treatments, alternative therapies are required. In this context, the investigators treated 11 patients with refractory chronic inflammatory CPPD with tocilizumab (TCZ), an anti-IL-6 receptor (IL-6R) monoclonal antibody. After 3 monthly infusions, improvement was estimated at over 75% (PMID 2213498). Our hypothesis is that inhibiting IL-6 is an effective therapeutic option in chronic inflammatory CPPD refractory to conventional therapies.

Main objective and primary endpoint:

• To demonstrate the efficacy of IL-6 inhibition in treatment-refractory chronic inflammatory forms of CPPD disease.
• Our endpoint will be the change in global pain VAS between initiation and M4, i.e. one month after the 3rd infusion. VAS will be assessed after 24 hours off analgesics.

Secondary objectives and endpoints:

• Efficacy: DAS28-CRP, number of swollen, painful joints, overall disease activity VAS, fatigue VAS; overall effect on pain: area under the VAS curve (AUC); proportion of patients responding from M2 to M6 (improvement ≥ 50% of initial pain VAS) and complete response (improvement ≥ 80% of initial pain VAS); relapse rate; improvement in quality of life (SF-36, HAQ, EQ-5D-3L questionnaires)
• Tolerance: infusion reactions, infections, neutropenia, hepatic cytolysis, lipid profile

This is a phase II, multicentre, randomized, controlled, double-blind, superiority study, including 2 parallel groups with a 1:1 distribution. This trial will involve adults suffering from the chronic inflammatory polyarticular form of CPPD disease.

This study will involve 80 participants recruited in 13 centres in France.

No informado en este registro.

Drug: Tocilizumab

No informado en este registro.

Other: Placebo

Tocilizumab, 8 mg/kg/month, IV infusion for 3 months

Tocilizumab, an anti-IL-6R monoclonal antibody, was approved in January 2009 for the treatment of rheumatoid arthritis. Its indications have since been extended, particularly for the treatment of giant cell arteritis, juvenile chronic arthritis, and severe cytokine release syndrome induced by chimeric antigen receptor T-cell (CAR-T) therapy.

Saline placebo, IV infusion / month for 3 months

Plazo: 6 months

Overall pain will be assessed, after 24 hours of discontinuation of analgesics, using a visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced), at inclusion, before each infusion at months M1, M2, M3, then at M4 (primary outcome) and M6.

Plazo: 6 months

Disease Activity Score (DAS28-CRP), number of swollen and painful joints, Patient assessment of overall disease activity by a visual analogue scale (VAS) ranging from 0 (no activity) to 100 mm (maximal activity). Those outcomes will be assessed at inclusion, before each infusion at months M1, M2, M3, then at M4 (primary outcome) and M6

Plazo: 6 months

Area under the curve (AUC) of the overall pain visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced) based on assessments at baseline, before each infusion at months M1, M2, M3 and at M4 and M6 (end of the study). Overall pain VAS will be collected after a 24-hour washout of analgesics.

Plazo: 6 months

Response to treatment will be defined as an improvement ≥ 50% of initial pain visual analogue scale (VAS) ranging from 0 (no pain) to 100 mm (worst pain ever experienced) Complete response will be defined as an improvement ≥ 80% of initial pain VAS This outcome will be assessed from M2 to M6.

Relapse will be assessed in responders at 6 months, and the time from response to relapse will be determined.

Plazo: 6 months

Outcome Measures - Inflammatory Biomarkers

Erythrocyte Sedimentation Rate (ESR) Unit: millimeters (mm) Frequency: measured at each visit

No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified.

Plazo: 6 months

Outcome Measures - Inflammatory Biomarkers

C-reactive Protein (CRP) Unit: milligrams per liter (mg/L) Frequency: measured at each visit

No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified.

Plazo: 6 months

Outcome Measures - Inflammatory Biomarkers

Interleukin-6 (IL-6) Unit: picograms per milliliter (pg/mL) Frequency: measured at each visit

No aggregation of this measure is planned to produce a composite value. If aggregation is considered (e.g., to generate an overall inflammation score), a validated statistical method will be specified.

Plazo: 6 months

Full Title: Short Form 36 Health Survey (SF-36) Scale Range: 0 to 100 per subscale Interpretation: Higher scores indicate better health status or quality of life Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Score

This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system.

Plazo: 6 months

Full Title: Health Assessment Questionnaire (HAQ) Scale Range: 0 to 3 Interpretation: Higher scores indicate worse functional ability (i.e., more disability) Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Score

This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system.

Plazo: 6 months

Full Title: EuroQol Five Dimensions Three Levels (EQ-5D-3L) Scale Range: 0 to 100 Interpretation: Higher scores indicate better health-related quality of life Time Points: Baseline, prior to each infusion, and at Months 4 and 6 (M4 and M6) Unit: Index value

This questionnaire will be analyzed and reported as a distinct outcome measure, in accordance with its specific scoring system.

Plazo: 6 months

Outcome Measure - Number of Participants with Adverse Events

Description: Number of participants experiencing any of the following safety-related events at each visit:

• Infusion reactions
• Neutropenia
• Thrombocytopenia
• Hepatic cytolysis
• Severe infections
• Treatment-related adverse events
• Abnormal changes in lipid profile

Unit of Measure: Count (participants) Time Points: Each visit Note: Each event type will be recorded and analyzed separately but reported under a unified outcome measure to reflect overall safety.

Plazo: 6 months

Description: Mean neutrophil count measured from blood samples collected at each visit.

Unit of Measure: normal: 2500-8000/μL; AE: \<1500/μL

Plazo: 6 months

Description: Mean platelet count measured from blood samples collected at each visit.

Unit of Measure: normal: 150,000-400,000/μL; AE: \<75,000/μL

Plazo: 6 months

Description: Mean levels of transaminases (e.g., ALT, AST) measured to assess hepatic cytolysis.

Unit of Measure: ALT/AST normal: \<40 U/L; AE: \>3×ULN

Plazo: 6 months

Description: Mean values of lipid profile components (e.g., total cholesterol, LDL, HDL, triglycerides) measured at each visit.

Unit of Measure: normal: TC \<200, LDL \<130, HDL \>45/55, TG \<150 mg/dL

Randomized, Double-blind, Multicentre Trial of Tocilizumab Versus Placebo in Chronic Polyarticular Inflammatory of Calcium Pyrophosphate Deposition Disease Refractory to Standard Treatments